Description (adapted from the application). The host and viral factors that predict progression of liver disease in humans with chronic hepatitis C are not well defined. HCV infection becomes chronic in about 80 percent of cases, and progressive liver disease develops over several decades in about 20 percent of chronically infected individuals. Host factors such as alcohol use, age and gender have been implicated as risk factors for progression of hepatitis C. However, investigation of host-viral interactions has been difficult due to the long natural history of disease and lack of well- preserved serum banks for longitudinal orological analyses. The experiments outlined in Project 3 are designed to determine whether levels of HCV replication (serum HCV RNA titers) and/or genetic variability within the HCV RNA genome are significant predictors of the long-term clinico- pathological outcome of chronic hepatitis C in humans. Three specific aims will be addressed. (1) Define the natural history of chronic hepatitis C in the Alaskan Native American (ANA) cohort, and assess the impact of epidemiological and host factors on viral replication and disease outcome. (2) Determine the longitudinal patterns of HCV viremia in subjects who develop progressive liver injury and in genotype-matched subjects who are disease non-progressors. (3) Determine the rates of HCV quasispecies genetic diversification over time in subjects who develop progressive liver injury and in genotype matched subjects who are disease non-progressors, and investigate the possibility that specific viral mutations may be either protective or detrimental to the infected host. The studies, which were initiated in 1996 on 110 subjects, are presently being conducted on stored serum specimens from over 500 subjects recruited into the ANA cohort. In all cases, HCV genotype and viremia status, date of first and most recent positive specimen, have been determined. In select cases with adequate sample storage and current liver biopsy results, longitudinal quantitative viremia profiles and quasispecies mutation patterns over 5-20 years will be characterized using molecular technologies. An extensive clinical and demographic database is under construction to allow detailed analysis of host-viral relationships important for progression of chronic hepatitis C. Data analyses will be conducted in collaboration with investigators at the Arctic Investigations Program (AIP) in Anchorage and the Viral Hepatitis Branch of the Centers for Disease Control and Prevention (CDC) and the Viral Hepatitis Program at the Alaska Native Medical Center (ANMC).